Open AccessCase report A possible new syndrome with growth-hormone secreting pituitary adenoma, colonic polyposis, lipomatosis, lentigines and renal carcinoma in association with famili
Trang 1Open Access
Case report
A possible new syndrome with growth-hormone secreting pituitary adenoma, colonic polyposis, lipomatosis, lentigines and renal
carcinoma in association with familial testicular germ cell
malignancy: A case report
Phuong L Mai*1, Larissa Korde1, Joan Kramer1, June Peters1,
Christine M Mueller1, Susan Pfeiffer2, Constantine A Stratakis3,
Peter A Pinto4, Gennady Bratslavsky4, Maria Merino5, Peter Choyke6, W
Address: 1 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health,
Bethesda, Maryland, USA, 2 Westat Incorporated, Rockville, Maryland, USA, 3 Section on Endocrinology & Genetics, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA, 4 Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA, 5 Division of Laboratory and Pathology, National
Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA and 6 Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
Email: Phuong L Mai* - maip@mail.nih.gov; Larissa Korde - Kordel@mail.nih.gov; Joan Kramer - jlk_otd@yahoo.com;
June Peters - petersju@mail.nih.gov; Christine M Mueller - muellerc@mail.nih.gov; Susan Pfeiffer - susan@karpfrosh.com;
Constantine A Stratakis - stratakc@mail.nih.gov; Peter A Pinto - pintop@mail.nih.gov; Gennady Bratslavsky - bratslag@mail.nih.gov;
Maria Merino - mjmerino@mail.nih.gov; Peter Choyke - pchoyke@mail.nih.gov; W Marston Linehan - linehanm@mail.nih.gov;
Mark H Greene - greenem@mail.nih.gov
* Corresponding author
Abstract
Background: Germ-cell testicular cancer has not been definitively linked to any known hereditary cancer susceptibility
disorder Familial testicular cancer in the presence of other findings in affected and unaffected family members might indicate a previously-unidentified hereditary cancer syndrome
Case presentation: The patient was diagnosed with a left testicular seminoma at age 28, and treated with left orchiectomy
followed by adjuvant cobalt radiation His family history is significant for testicular seminoma in his son, bladder cancer in his sister, and lipomatosis in his father His evaluation as part of an etiologic study of familial testicular cancer revealed multiple colon polyps (adenomatous, hyperplastic, and hamartomatous) first found in his 50 s, multiple lipomas, multiple hyperpigmented skin lesions, left kidney cancer diagnosed at age 64, and a growth-hormone producing pituitary adenoma with associated
acromegaly diagnosed at age 64 The patient underwent genetic testing for Cowden syndrome (PTEN gene), Carney complex (PRKAR1A gene), and multiple endocrine neoplasia syndrome type 1 (MEN1 gene); no deleterious mutations were identified.
Discussion: The constellation of benign and malignant neoplasms in the context of this patient's familial testicular cancer raised
the possibility that these might be manifestations of a known hereditary susceptibility cancer syndrome; however, genetic testing for the three syndromes that were most likely to explain these findings did not show any mutation Alternatively, this family's phenotype might represent a novel neoplasm susceptibility disorder This possibility cannot be evaluated definitively on the basis
of a single case report; additional observations and studies are necessary to investigate this hypothesis further
Published: 28 March 2007
Journal of Medical Case Reports 2007, 1:9 doi:10.1186/1752-1947-1-9
Received: 6 February 2007 Accepted: 28 March 2007 This article is available from: http://www.jmedicalcasereports.com/content/1/1/9
© 2007 Mai et al; licensee BioMed Central Ltd
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Trang 2Testicular germ cell tumor (TGCT) is the most common
malignancy in U.S adolescents and young adult males
ages 15–45 TGCT risk factors include family history,
per-sonal history of previously-diagnosed TGCT,
cryp-torchidism and other disorders of male urogenital
differentiation [1]
Approximately 1–3% of individuals with TGCT report
having ≥ one affected first-degree relative The relative risk
of TGCT is higher among siblings than among fathers or
sons of affected individuals [1], suggesting the possibility
of genetic heterogeneity and environmental influences
Segregation analysis suggested that genetic susceptibility
is important in familial TGCT, with recent studies
indicat-ing that multiple genetic loci of lower penetrance actindicat-ing in
concert contribute to the familial aggregation of this
malignancy [2] Although TGCT has been implicated in a
number of genetic disorders, it has not been definitively
linked to any known hereditary cancer syndrome [3]
Finally, individuals with TGCT are observed to have
increased risks of certain cancers, including pancreas,
kid-ney, urinary bladder, thyroid, lymphatic tissue, leukemia,
and connective tissues [4] Although the excess risk of
sev-eral of these second malignancies has been attributed to
late complications of testicular cancer treatment, the
pos-sibility that TGCT is part of a familial syndrome which
includes other types of cancer cannot be dismissed
We established the Multidisciplinary Etiologic Study of Familial Testicular Cancer in 2002 (NCI Protocol 02-C-0178) to identify possible testicular cancer susceptibility genes and to characterize more precisely the clinical phe-notype of the familial testicular cancer syndrome During the course of this study, we encountered a family with seminoma in a father and son, and a provocative constel-lation of other cancers and benign conditions in the father The following case report summarizes our attempt
to explain these findings on the basis of a known cancer susceptibility disorder
Case report
The proband was a 63 year-old, Caucasian male who pre-sented to the NCI Clinical Genetics Branch in October
2004 for evaluation of familial testicular cancer He devel-oped a left testicular pure seminoma at age 28 (per medi-cal records; no pathology was available for review); he underwent a left radical orchiectomy followed by adju-vant cobalt irradiation to the retroperitoneum, and has remained free of testicular cancer
At his initial NIH visit, the patient reported resection of multiple colonic polyps on successive colonoscopies, beginning in his early 50 s Materials from several excised polyps were reviewed at the NIH Laboratory of Pathology, and revealed a mixed polyposis of 5 adenomatous polyps,
2 hamartomatous polyps (Figure 1a), and multiple hyper-plastic polyps
Photomicrographs
Figure 1
Photomicrographs (a) Haematoxylin and Eosin stain (100×) of a hamartomatous polyp from the descending colon showed
proliferation of dilated mucinous glands surrounded by smooth muscle fibers This latter feature is characteristic of hamar-tomatous polyps observed in patients with Peutz-Jegher syndrome (b) Photomicrograph of the left kidney tumor was com-posed of a solid proliferation of spindle cell with large irregular nucleus, abundant cytoplasm, and prominent mitotic figures The findings are consistent with a high-grade clear cell renal cell carcinoma, sarcomatoid type
Trang 3Physical examination revealed a muscular, mesomorphic
white male (he is an avid body-builder) with multiple
subcutaneous lipomas in the extremities and trunk He
had multiple dark brown to black, irregularly-shaped
pig-mented macules on the chest, back, arms, and legs, which
were clinically suggestive of dysplastic nevi Biopsy of the
clinically most atypical lesion showed a simple lentigo,
without melanocytic atypia Protocol-related blood work,
including testosterone, estradiol, chemistry panel,
pros-tate specific antigen, alpha-fetoprotein, follicle
stimulat-ing hormone, luteinizstimulat-ing hormone, and beta-HCG, were
normal Ultrasound of the right testis showed early
micro-lithiasis Computed tomography of the chest, abdomen,
and pelvis revealed an unexpected left inferomedial renal
mass (Figure 2b), which was confirmed by MRI Further evaluation of the left kidney mass was recommended, but not pursued due to other medical issues
He returned for a scheduled clinic visit one year later and reported having an elevated growth hormone (GH) level detected during a complementary/alternative health eval-uation The patient also stated that his head and hands had been "getting bigger" He reported taking various die-tary supplements, none of which was found to contain androgens upon review of their ingredients, as well as tes-tosterone gel, which was started at the time of his comple-mentary/alternative health evaluation due to a low serum testosterone level On examination, he had an
acromeg-Imaging studies
Figure 2
Imaging studies (a) MRI of pituitary adenoma – T1 weighted sagittal MRI of the pituitary gland after intravenous contrast
reveals an enlarged gland that is centrally hypoenhancing, with a rim of relative hyper-enhancement at the superior margin The longest dimension of the pituitary is approximately 2 cm (b) Composite of CT images of the left kidney, first visit and one year later- Serial contrast media-enhanced CTs of the abdomen demonstrate an enlarging left renal mass The initial scan (October 2004) demonstrates a solid enhancing mass (white arrow) measuring approximately 2.6 cm Follow-up CT approximately one year later shows slight enlargement (3.0 cm) (white arrow)
Trang 4alic appearance, including protruding supra-orbital
ridges, a prognathic jaw, wide nose, and diffuse soft-tissue
thickening of the hands, all of which were judged
clini-cally to be more prominent when compared with the year
before
Laboratory studies demonstrated a normal fasting
glu-cose, elevated levels of insulin-like growth factor-I (IGF-I)
[943 ng/ml; normal range 71–290 ng/ml] and IGF
bind-ing protein-3 [8.4 µg/ml; normal range 3.2–6.6 µg/ml] A
pituitary MRI revealed a hypoenhancing,
diffusely-enlarged pituitary measuring approximately 2 cm,
consist-ent with an adenoma (Figure 2a) A follow-up renal CT
showed the left inferomedial kidney mass had grown
compared with the study performed one year earlier; the
adrenal glands were normal
On January 23, 2006, the patient underwent
trans-sphe-noidal resection of the pituitary mass, yielding a
GH-pro-ducing adenoma On February 22, 2006, he underwent a
left nephrectomy for a stage III, poorly-differentiated renal
cell carcinoma, with sarcomatoid features (Figure 1b) By
November 2006, his growth hormone levels had returned
to normal, and he had no evidence of recurrent kidney
cancer
Detailed family history review revealed a son with
semi-noma (confirmed by outside pathology report) at age 34
(cancer-free at age 36), and a sister who developed urinary
bladder cancer (death certificate confirmation) at age 53
His son had no evidence of lipomatosis or multiple
lentig-ines on examination at the time of study enrollment, and
has had a negative screening colonoscopy The proband's
father was reported to have lipomatosis, but was
deceased There is no history of other benign or malignant
neoplasms reported in the rest of the family
Based on his personal history of multiple cancers, a
pitui-tary adenoma, multiple pigmented skin lesions, multiple
lipomas, and multiple colon polyps with varying
histol-ogy, the patient underwent genetic testing for Cowden
syndrome (the PTEN gene), Carney complex (the
PRKAR1A gene), and multiple endocrine neoplasia
syn-drome type 1 (the MEN1 or menin gene) No germline
mutations were detected in any of these genes
Discussion and conclusion
Our patient presented with multiple malignant and
benign neoplasms including left testicular seminoma, left
kidney renal cell carcinoma, a growth hormone-secreting
pituitary adenoma, multiple pigmented skin lesions,
lipo-mas, and colon polyps with varying histology
(adenoma-tous, hyperplastic, and hamartomatous) The proband's
son had testicular cancer and microlithiasis, but none of
the other neoplasms, and his father is reported to have
had lipomatosis The clinical phenotype of the familial TGCT syndrome, as currently understood, is comprised of
a site-specific predisposition to TGCT and does not appear
to include an increased risk for other benign or malignant neoplasms [1,3] Various aspects of testicular dysgenesis and genitourinary development have been implicated in the pathogenesis of familial TGCT, but this hypothesis remains unproven at present As part of the protocol under which the current family was seen, we have evalu-ated 136 members of 35 multiple-case TGCT families, including 56 men with a history of TGCT; the constella-tion of abnormalities seen in the proband reported here is unique in our experience (Korde L, Kramer J, Mueller CM, and Greene MH, personal communication) Therefore, the possibility that the neoplasms observed in this patient represent unrecognized manifestations of the familial TGCT syndrome seems unlikely
We considered whether these observations might be explained on the basis of a known genetic cancer suscep-tibility disorder and felt that Cowden syndrome, Carney complex, and multiple endocrine neoplasia type 1 war-ranted serious consideration in this regard, although none can account for all of the findings described herein (Table 1)
Cowden syndrome (CS), an autosomal dominant disease
associated with mutations in the PTEN tumor suppressor
gene on chromosome 10q10.22-23, is associated with ele-vated risks of breast and thyroid cancer, as well as diverse benign neoplasms including gastrointestinal hamartoma-tous polyps, lipomas, giant fibroadenomas of the breast, hemangiomas, and multiple early-onset uterine leiomyo-mas [5] Kidney cancer and testicular neoplasm have been reported in patients with CS, but their association with this syndrome remains unproven Our patient had multi-ple lipomas and colonic hamartomatous polyps, both of which are consistent with CS, but his renal cancer and pituitary adenoma cannot be readily explained on that basis The patient's kidney cancer was located in an area of the kidney that is likely to have been included within the field of radiation delivered to the retroperitoneum (port films could not be located) Increased risk of second pri-mary kidney cancer (RR = 2.8; 95% CI 2.1–3.8) among TGCT patients treated with post-operative radiation has been reported [4] Therefore, the renal cancer could be a late complication of anti-cancer therapy, rather than a component of a genetic syndrome The patient underwent commercial genetic testing for germline mutations in the
PTEN gene, with no mutation detected However, a
muta-tion is identified by convenmuta-tional testing in only 80% of patients who meet the CS clinical criteria, as they can have
a large deletion or mutations in the promoter region of
PTEN Consequently, CS has not been completely
Trang 5excluded, but this diagnosis is unlikely since his family
does not meet the clinical diagnostic criteria
Carney complex (CNC) is a multiple neoplasia syndrome
characterized by skin lesions (e.g., lentigines, compound
nevi, and blue nevi), psammomatous melanotic
schwan-noma, cardiac myxomas, large-cell calcifying Sertoli cell
tumors and Leydig cell tumors of the testis, as well as
endocrine tumors, including primary pigmented nodular
adrenocortical disease and pituitary adenoma, most of
which are GH-producing [6,7] CNC is associated with
germline mutations in the PRKAR1A gene on
chromo-some 17q22-24, which are detected in 50–65% of CNC
patients [6] About 30% of CNC families have been linked
to a susceptibility locus on chromosome 2p16 (CNC2),
but the gene at this locus has not yet been identified Our
patient had a GH-producing pituitary adenoma and
testic-ular cancer However, CNC does not include colon
pol-yps, lipomas or renal cancer among its recognized
manifestations He underwent testing for germline
muta-tions in the PRKAR1A gene; no mutation was identified.
Multiple endocrine neoplasia type 1 (MEN1) involves
tumors of the parathyroid, endocrine pancreas, anterior
pituitary, adrenal glands, and carcinoid tumors of the GI
tract It is associated with germline mutations in the
MEN1 gene, on chromosome 11q13 [8] Anterior
pitui-tary adenomas, about 1/4 of which are GH-producing, are
found in 10%–60%, and multiple lipomas are found in
about 30% of patients with MEN1 [8] Both the patient
and his father had multiple lipomas The father was not
known to have manifested other signs or symptoms
sug-gestive of MEN1 The patient underwent germline
muta-tion testing of the MEN1 gene, with no mutamuta-tion detected.
AIP (which encodes for the aryl hydrocarbon
receptor-interacting protein) has recently been implicated as a
low-penetrance, familial pituitary adenoma susceptibility gene [9] Although there are no other cases of pituitary ade-noma in this family, it is not presently known whether other neoplasms occur excessively in pituitary adenoma kindred We therefore tested the patient for mutations in
AIP; none were detected (CA Stratakis, personal
commu-nication)
Finally, testicular germ cell tumor has been described in acromegalic patients [10] Renal cancer, colon cancer, and colon polyps have been reported to occur excessively in acromegaly; however, the polyps observed in acromegalic patients are adenomatous or hyperplastic; hamartoma-tous polyps have not been described in this context [11,12] Our patient's seminoma was unlikely to be related to acromegaly, given the temporal sequence of events, and neither lipomatosis nor lentigines are part of the acromegaly phenotype However, we can not rule out the possibility of an association between acromegaly and either renal cancer and/or adenomatous and hyperplastic colon polyps in this patient
While our patient had some of the clinical features associ-ated with each of these cancer susceptibility disorders, none can account for his entire clinical phenotype, and germline mutation testing of the three genes implicated in the inherited diseases was negative Conventional clinical mutation testing may have failed to detect a mutation in one of these genes; however, this likelihood is small since his family does not meet the clinical diagnostic criteria for any of these syndromes He might represent an atypical presentation of some other known, multiple benign and malignant neoplasm susceptibility disorders (e.g., juve-nile polyposis syndrome, Peutz-Jeghers syndrome,
hered-itary hemorrhagic telangiectasia, or MYH-adenomatous
polyposis); research evaluation of a wider spectrum of genes is now underway Or, he may have several
co-exist-Table 1: Summary of patient's clinical findings relative to acromegaly and the three hereditary cancer susceptibility syndromes considered
Patient's Findings Acromegaly Hereditary Syndrome
Cowden syndrome Carney complex MEN1
Colon adenomatous polyps XX
Colon harmatomatous polyps XX
Colon hyperplastic polyps
XX: Classical syndrome-related findings
X: Findings are less clearly established as part of the syndrome
* Testicular cancers associated with Carney complex are typically large-cell calcifying Sertoli cell tumors or Leydig cells tumors of the testis
Trang 6Publish with Bio Med Central and every scientist can read your work free of charge
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ing but etiologically-unrelated conditions, e.g., familial
testicular cancer; acromegaly with renal cancer and colon
polyps; and idiopathic lipomatosis
The final possibility is that this family's phenotype
repre-sents a novel neoplasm susceptibility disorder, of which
TGCT is an important component Of course, this
hypoth-esis cannot be tested on the basis of a single case report
We await with interest future observations from other
clinical investigators, in response to the report we have
provided herein
Competing interests
The author(s) declare that they have no competing
inter-ests
Authors' contributions
PM had primary responsibility for drafting the
manu-script LK, JK, and MHG were responsible for the design
and operation of the Familial Testicular Cancer Study,
contributed to this patient's evaluation, and contributed
to writing the manuscript JP, CM, and SP were involved
in this patient's evaluation, genetic counseling, and data
collection and medical record abstraction CS evaluated
the patient for acromegaly and performed genetic testing
for Carney complex, MEN 1, and familial pituitary
ade-noma PP, WML, GB, MM, and PC were involved in the
patient's clinical assessment and treatment All authors
read and approved the final manuscript
Acknowledgements
The authors express their deepest appreciation to all of the participants in
our Familial Testicular Cancer study, without whose selfless contributions
of time, energy, and acceptance of disruptions in daily life this research
project could not have been accomplished Written informed consent was
obtained from the patient both for publication of the case report as well as
for use of clinical images in this report We are particularly indebted to him
and to his relatives for their unique contribution to our research Finally,
the hard work and dedication of research support staff from Westat, Inc,
including Ron Kase, Rissah Watkins, Beth Mittl and Ann Carr, are gratefully
acknowledged.
This research was funded by the Intramural Research Program of the
National Cancer Institute, National Institutes of Health, and supported by
Contract N02-CP-11019-50, with Westat, Incorporated.
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